In this renewal application we designed experiments aimed to capitalize on two major advances which occurred during the last funding period; 1. HGF biology: Hepatocyte Growth Factor (HGF) is now fully cloned and sequenced, in part from work funded by this grant in its earlier periods. Its receptor (encoded by the proto-oncogene c-met) is now well characterized. Activation of HGF by urokinase is now well documented. 2. In its new location in the university of Pittsburgh the lab has now access to hepatic tissue from the largest liver transplantation program in the world. Approximately 450 cases of liver at end stages of disease is available annually. The lab has now access to an existing collection of frozen tissue and paraffin blocks from hundreds of well defined stages of human hepatic disease. It also has access to all the new livers resected from transplantation cases. The project is now focusing on utilizing the new knowledge on HGF biology and the access of human liver tissues to focus on two lethal forms of human liver disease where growth disregulation leads to death: A. Hepatocellular Carcinoma (HCC). This is the most frequent cancer in the world. HGF is mitogenic and motogenic in normal human hepatocytes but is only motogenic and sometimes mitoinhibitory in human hepatocellular carcinomas. We will examine the role of HGF as a mitogen, motogen and mitoinhibitor in the evolution of human hepatocellular carcinoma from its earliest stages (atypical adenomatous hyperplasia, (AAH) seen as solitary nodules in cirrhosis), to its most advanced widely invasive forms. The role of HGF activation by urokinase in the evolution of this disease will be also examined. The potential mitoinhibitory effects of HGF on HCC, if properly documented understood, may have a therapeutic potential in this disease. B. Fulminant liver Failure (FHF): In this condition, hepatocyte regeneration ceases, stem cell compartment (ductular hepatocytes) becomes activated, solitary clonal growths of hepatocytes (pseudoadenomas) grow to a hugh size. HGF levels in the plasma are extremely high. We will investigate; a. the role of HGF as a mitogen, motogen and morphogen in the evolution of new cell populations in this disease; b. the role of high doses of HGF in the inhibition of hepatocyte regeneration (leading to death of the patient); c. the effect of high doses of HGF in the activation of the stem cell compartment in the human liver.